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The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres
Author(s) -
Gruber R.,
Carmeliet E.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb11921.x
Subject(s) - disopyramide , sodium channel , depolarization , chemistry , membrane potential , biophysics , hyperpolarization (physics) , purkinje fibers , voltage clamp , time constant , sodium , stimulation , sodium channel blocker , electrophysiology , medicine , biochemistry , stereochemistry , biology , organic chemistry , engineering , nuclear magnetic resonance spectroscopy , electrical engineering
1 The effect of disopyramide on the maximum upstroke velocity () and the sodium current of rabbit cardiac Purkinje fibres was studied with the two‐microelectrode voltage‐clamp technique. 2 In the absence of stimulation the drug did not cause block at membrane potentials ranging from −100 to −65 mV. Use‐dependent block of was most pronounced at −75 mV. At hyperpolarized membrane potentials development of use‐dependent block was faster than at depolarized membrane potentials. The time course of development of use‐dependent block was not significantly influenced by the duration of the depolarizing pulse. These results strongly suggest that disopyramide predominantly blocks activated sodium channels. 3 The relative decrease of the sodium current at the beginning of a 2 s depolarizing clamp to −45 mV was almost the same as at the end, implying a rapid blockade of activated sodium channels. The Hill plots were linear with slopes ranging from 0.98 to 1.08 indicating a first order reaction; the dissociation constant for activated channels was 70 μ m . 4 Recovery of from use‐dependent block during rest was strongly voltage‐dependent, the time constant of recovery increasing upon hyperpolarization. When the fraction of charged molecules was reduced by changing the pH of the external solution, the voltage‐dependence of recovery was decreased. In contrast, recovery of for a change in holding potential from −80 to −95 mV was very fast during repetitive stimulation. 5 It is concluded that disopyramide blocks the sodium channel during activation and is trapped in the channel when the activation gate closes.